8q8k

From Proteopedia

(Difference between revisions)

Current revision

KI Polyomavirus LTA NLS bound to importin alpha 2

Structural highlights

8q8k is a 4 chain structure with sequence from KI polyomavirus Stockholm 60 and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LT_POVK6 Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Has processive 3'-5' DNA helicase activity which requires a short 3' single-stranded region and ATP. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription.[UniProtKB:P03070]

Publication Abstract from PubMed

Nucleocytoplasmic transport regulates the passage of proteins between the nucleus and cytoplasm. In the best characterized pathway, importin (IMP) alpha bridges cargoes bearing basic, classical nuclear localization signals (cNLSs) to IMPbeta1, which mediates transport through the nuclear pore complex. IMPalpha recognizes three types of cNLSs via two binding sites: the major binding site accommodates monopartite cNLSs, the minor binding site recognizes atypical cNLSs, while bipartite cNLSs simultaneously interact with both major and minor sites. Despite the growing knowledge regarding IMPalpha-cNLS interactions, our understanding of the evolution of cNLSs is limited. We combined bioinformatic, biochemical, functional, and structural approaches to study this phenomenon, using polyomaviruses (PyVs) large tumor antigens (LTAs) as a model. We characterized functional cNLSs from all human (H)PyV LTAs, located between the LXCXE motif and origin binding domain. Surprisingly, the prototypical SV40 monopartite NLS is not well conserved; HPyV LTA NLSs are extremely heterogenous in terms of structural organization, IMPalpha isoform binding, and nuclear targeting abilities, thus influencing the nuclear accumulation properties of full-length proteins. While several LTAs possess bipartite cNLSs, merkel cell PyV contains a hybrid bipartite cNLS whose upstream stretch of basic amino acids can function as an atypical cNLS, specifically binding to the IMPalpha minor site upon deletion of the downstream amino acids after viral integration in the host genome. Therefore, duplication of a monopartite cNLS and subsequent accumulation of point mutations, optimizing interaction with distinct IMPalpha binding sites, led to the evolution of bipartite and atypical NLSs binding at the minor site.

A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin alpha-dependent nuclear localization signals.,Cross EM, Akbari N, Ghassabian H, Hoad M, Pavan S, Ariawan D, Donnelly CM, Lavezzo E, Petersen GF, Forwood JK, Alvisi G Protein Sci. 2024 Feb;33(2):e4876. doi: 10.1002/pro.4876. PMID:38108201^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cross EM, Akbari N, Ghassabian H, Hoad M, Pavan S, Ariawan D, Donnelly CM, Lavezzo E, Petersen GF, Forwood JK, Alvisi G. A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin α-dependent nuclear localization signals. Protein Sci. 2024 Feb;33(2):e4876. PMID:38108201 doi:10.1002/pro.4876

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8q8k"

@@ Line 1: / Line 1: @@
-==n/a==
+==KI Polyomavirus LTA NLS bound to importin alpha 2==
-<StructureSection load='8q8k' size='340' side='right'caption='[[8q8k]]' scene=''>
+<StructureSection load='8q8k' size='340' side='right'caption='[[8q8k]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8Q8K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Q8K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[8q8k]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/KI_polyomavirus_Stockholm_60 KI polyomavirus Stockholm 60] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8Q8K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Q8K FirstGlance]. <br>
-</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8q8k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8q8k OCA], [https://pdbe.org/8q8k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8q8k RCSB], [https://www.ebi.ac.uk/pdbsum/8q8k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8q8k ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/LT_POVK6 LT_POVK6] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Has processive 3'-5' DNA helicase activity which requires a short 3' single-stranded region and ATP. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription.[UniProtKB:P03070]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Nucleocytoplasmic transport regulates the passage of proteins between the nucleus and cytoplasm. In the best characterized pathway, importin (IMP) alpha bridges cargoes bearing basic, classical nuclear localization signals (cNLSs) to IMPbeta1, which mediates transport through the nuclear pore complex. IMPalpha recognizes three types of cNLSs via two binding sites: the major binding site accommodates monopartite cNLSs, the minor binding site recognizes atypical cNLSs, while bipartite cNLSs simultaneously interact with both major and minor sites. Despite the growing knowledge regarding IMPalpha-cNLS interactions, our understanding of the evolution of cNLSs is limited. We combined bioinformatic, biochemical, functional, and structural approaches to study this phenomenon, using polyomaviruses (PyVs) large tumor antigens (LTAs) as a model. We characterized functional cNLSs from all human (H)PyV LTAs, located between the LXCXE motif and origin binding domain. Surprisingly, the prototypical SV40 monopartite NLS is not well conserved; HPyV LTA NLSs are extremely heterogenous in terms of structural organization, IMPalpha isoform binding, and nuclear targeting abilities, thus influencing the nuclear accumulation properties of full-length proteins. While several LTAs possess bipartite cNLSs, merkel cell PyV contains a hybrid bipartite cNLS whose upstream stretch of basic amino acids can function as an atypical cNLS, specifically binding to the IMPalpha minor site upon deletion of the downstream amino acids after viral integration in the host genome. Therefore, duplication of a monopartite cNLS and subsequent accumulation of point mutations, optimizing interaction with distinct IMPalpha binding sites, led to the evolution of bipartite and atypical NLSs binding at the minor site.
+A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin alpha-dependent nuclear localization signals.,Cross EM, Akbari N, Ghassabian H, Hoad M, Pavan S, Ariawan D, Donnelly CM, Lavezzo E, Petersen GF, Forwood JK, Alvisi G Protein Sci. 2024 Feb;33(2):e4876. doi: 10.1002/pro.4876. PMID:38108201<ref>PMID:38108201</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 8q8k" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: KI polyomavirus Stockholm 60]]
 [[Category: Large Structures]]
-[[Category: N/a]]
+[[Category: Mus musculus]]
+[[Category: Alvisi G]]
+[[Category: Cross EM]]
+[[Category: Forwood JK]]

8q8k

From Proteopedia

Current revision

KI Polyomavirus LTA NLS bound to importin alpha 2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox